Function and mechanism of toll-like receptors in cerebral ischemic tolerance: from preconditioning to treatment

Abstract

Increasing evidence suggests that toll-like receptors (TLRs) play an important role in cerebral ischemia-reperfusion injury. The endogenous ligands released from ischemic neurons activate the TLR signaling pathway, resulting in the production of a large number of inflammatory cytokines, thereby causing secondary inflammation damage following cerebral ischemia. However, the preconditioning for minor cerebral ischemia or the preconditioning with TLR ligands can reduce cerebral ischemic injury by regulating the TLR signaling pathway following ischemia in brain tissue (mainly, the inhibition of the TLR4/NF-κB signaling pathway and the enhancement of the interferon regulatory factor-dependent signaling), resulting in TLR ischemic tolerance. Additionally, recent studies found that postconditioning with TLR ligands after cerebral ischemia can also reduce ischemic damage through the regulation of the TLR signaling pathway, showing a significant therapeutic effect against cerebral ischemia. These studies suggest that the ischemic tolerance mediated by TLRs can serve as an important target for the prevention and treatment of cerebral ischemia. On the basis of describing the function and mechanism of TLRs in mediating cerebral ischemic damage, this review focuses on the mechanisms of cerebral ischemic tolerance induced by the preconditioning and postconditioning of TLRs and discusses the clinical application of TLRs for ischemic tolerance.

Figure 1

Schematic of TLR signaling and gene expression following stroke. (A) TLR4 signaling cascades following stroke. Stroke leads to NF-κB activation without IRF3 activation. (B) LPS (CpG) preconditioning prior to stroke leads to robust activation of IRF3 and type I interferon; meanwhile, the increased Ship1, Tollip, and p105 lead to the suppression of NF-κB activity and pro-inflammation cytokines compared to stroke alone. (C) Pam3CSK4 preconditioning activates the TLR2/PI3K/Akt signaling pathway and subsequently downregulates NF-κB activity and the expression of Bax, as well as increases the expression of Bcl-2, Hsp27, and Hsp70. (D) Poly-IC preconditioning activates IRF3 and induces IFN-β production. (E) GDQ preconditioning activates IRF7 and induces IFN-α production. DAMPs, damage-associated molecular patterns; TLR, toll-like receptor; TRIF, TIR-domain-containing adapter-inducing interferon-β; IRF, interferon regulatory factor; LPS, lipopolysaccharide; Poly-IC, polycytidylic acid; .

Figure 2

Poly-IC postconditioning activates the TLR3/IRF3 signaling pathway and increases the IFN-β levels and subsequently downregulates TLR/NF-κB signaling to decrease the levels of pro-inflammatory cytokines. DAMPs, damage-associated molecular patterns; TLR, toll-like receptor; TRIF, TIR-domain-containing adapter-inducing interferon-β; IRF, interferon regulatory factor; IFN, interferon; Poly-IC, polycytidylic acid.